Ring d-seco-19-nor-androstane derivatives



United States Patent "ice Panama. N0 Drawing. Filed Dec. 11, 1961, Ser.No. 158,538 2 Claims. (Cl. 260--514.5)

The present invention relates to novel cyclopentand phenanthrenederivatives and to a process for the produc- -.tion thereof. Moreparticularly the present invention relates to ringD-seco-l9-nor-androstane derivatives.

The novel compounds of the present invention, which are anti-androgenicagents and also exhibit anti-gonadotrophic properties, are representedby the following for- Inulas:

The novel compounds represented by the above formulas are prepared bythe process exemplified by the following equation:

In practicing the process outlined above the starting compound, which is16,17-seco-A -estratrien-3-ol- 3 7 l 25 7 Patented June 29,: 1965 17-oicacid (I), is treated with dimethyl sulfate in a strongly basic medium,such as potassium hydroxide solution, thus affordingl6,l7-seco-3-methoxy-A -estratrien-17-oic acid (II). Treatment of thiscompound by the Birch procedure, namely with lithium in liquid am monia,furnished the corresponding 3-methoxy-A compound which, upon hydrolysisin a strongly acid medium such as hydrochloric acid, gives16,17-seco-l9-nor- A -androsten-3-one-17-oic acid (III). Reaction ofthis compound or the sodium salt thereof with oxalyl chloride yields thecorresponding acyl chloride (IV) which upon treatment with dimethylcadmium in a suitable solvent such as ether for a period of time of theorder of 20 hours gives l7-methyl-16,17-seco-19-nor-A-androstene-3,17-dione (V).

Example I To a boiling solution of 5 g. of 16,l7seco-Aestratrien-3-ol-17-oic acid in 500 cc. of ethanol were added a total of20 cc. of dimethyl sulfate and a solution of 80 g. of potassiumhydroxide in 50 cc. of water, with continued boiling. The two liquidswere added alternatively in portions of 5 cc. of each over a period of30 minutes. The mixture was boiled for a further minutes, then cooled,poured into ice water and neutralized with hydrochloric acid. Theresulting precipitate was collected, washed with water and dried.Crystallization from chloroform-methanol gave 16,17-seco-3-methoxy- A-estratrieu-l7-oic acid.

Example I! A cold solution of 5 g. of the foregoing steroid in 750 cc.of anhydrous ether was added to 900 cc. of liquid ammonia and then 7.0g. of lithium Wire over 10 minutes, with constant stirring. The mixturewas stirred for 20 minutes more, 160 cc. of absolute ethanol were thencautiously added and the ammonia was allowed to evaporate. Water wasadded to the residue, the ether distilled off and the resulting16,17-seco-3-methoxy-A -estradien-l7-oic acid collected, washed withwater and dried.

A mixture containing the above compound, 220 cc. of methanol and 132 0c.of 3 N hydrochloric acid was heated at 60 C. for 18 minutes. Thesolution was cooled, poured into iced water and the resultingprecipitate was collected, washed with water and dried. Crystallizationfrom acetone-hexane yielded 16,17-seco-19-nor-.M-androsten-Ii-one-l7-oic acid.

Example III 3 g. of the foregoing compound in cc. of absolute ethanolcontaining 1 molar equivalent of sodium ethoxide was refluxed for 2hours and then evaporated to dryness under high vacuum.

A mixture of 2 g. of the crude sodium salt and 10 cc. of oxalyl chloridewas kept under anhydrous conditions and at room temperature during 2hours. The solution was evaporated in vacuum, 2 portions of dry benzenewere added and reevaporated to eliminate traces of oxalyl chloride, thusaffording 16,17-seco-19-nor-A -androsten3- one-l7-oic acyl chloride.

Example IV A solution of 1 g. of the acyl chloride in 50 cc. ofanl1ydrous ether was added to a refluxing solution of 5 g. of dimethylcadmium [1. Cason, I. Am. Chem. Soc. 68, 2078 (1946)] in 500 cc. ofanhydrous ether. After refluxing for 20 hours the mixture was pouredinto dilute aqueous hydrochloric acid. Ether extraction followed bywashing to neutrality and evaporation of the solvent provided a crudeproduct which upon recrystallization from ether-hexane yieldedl7-methyl-l6,l7-seco-19-nor-A -androstene-3,17'dione.

3,192,257 3 4 I claim: OTHER REFERENCES 1. 16,17-S6CO-19-I1OI-A-a11dI'OSteI1-3-OI16-17-OiC acid. Fiaser et 1 s i H 959 pp. 592 5 2.17-methy1 16,17 seco-19-nor-M-androstene-3,17-

dione. LORRAINE A. WEINBERGER, Acting Primary Exam- References Cited bythe Examiner 5 UNITED STATES PATENTS CHARLES B. PARKER, LEON ZITVER,Examiners.

2,830,074 4/58 Farinacci 260-5145 X

1. 16,17-SECO-19-NOR-$4-ANDROSTEN-3-ONE-17-OIC ACID. 2.17-METHYL-16,17-SECO-19-NOR-$4-ANDROSTENE-3-17DIONE.